ResearchPad - molecular-structure https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[A conformation-based intra-molecular initiation factor identified in the flavivirus RNA-dependent RNA polymerase]]> https://www.researchpad.co/article/elastic_article_14506 The function of a protein is often dictated by a single defined fold, which in turn is determined by its amino acid sequences. However, multiple global conformations can be utilized by a protein to fulfill distinct functions under different circumstances. The flavivirus NS5 protein, a natural fusion of an N-terminal methyltransferase (MTase) and a C-terminal RNA-dependent RNA polymerase (RdRP), may be such an example. Previously reported NS5 crystal structures exhibit two apparently different global conformations. In this work, we demonstrate that both conformations are conserved in the flaviviruses and important for virus proliferation, but only one of them is clearly relevant to RdRP catalysis, in particular at the early stages of the RNA synthesis.

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<![CDATA[Cobalt ion interaction with TMEM16A calcium-activated chloride channel: Inhibition and potentiation]]> https://www.researchpad.co/article/Nba3bff3f-41a4-460d-bc9b-3a7adada8996

TMEM16A, a Ca2+-sensitive Cl- channel, plays key roles in many physiological functions related to Cl- transport across lipid membranes. Activation of this channel is mediated via binding intracellular Ca2+ to the channel with a relatively high apparent affinity, roughly in the sub-μM to low μM concentration range. Recently available high-resolution structures of TMEM16 molecules reveal that the high-affinity Ca2+ activation sites are formed by several acidic amino acids, using their negatively charged sidechain carboxylates to coordinate the bound Ca2+. In this study, we examine the interaction of TMEM16A with a divalent cation, Co2+, which by itself cannot activate current in TMEM16A. This divalent cation, however, has two effects when applied intracellularly. It inhibits the Ca2+-induced TMEM16A current by competing with Ca2+ for the aforementioned high-affinity activation sites. In addition, Co2+ also potentiates the Ca2+-induced current with a low affinity. This potentiation effect requires high concentration (mM) of Co2+, similar to our previous findings that high concentrations (mM) of intracellular Ca2+ ([Ca2+]i) can induce more TMEM16A current after the Ca2+-activation sites are saturated by tens of μM [Ca2+]i. The degrees of potentiation by Co2+ and Ca2+ also roughly correlate with each other. Interestingly, mutating a pore residue of TMEM16A, Y589, alters the degree of potentiation in that the smaller the sidechain of the replaced residue, the larger the potentiation induced by divalent cations. We suggest that the Co2+ potentiation and the Ca2+ potentiation share a similar mechanism by increasing Cl- flux through the channel pore, perhaps due to an increase of positive pore potential after the binding of divalent cations to phospholipids in the pore. A smaller sidechain of a pore residue may allow the pore to accommodate more phospholipids, thus enhancing the current potentiation caused by high concentrations of divalent cations.

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<![CDATA[The molecular structure of β-alanine is resistant to sterilising doses of gamma radiation]]> https://www.researchpad.co/article/5c478c76d5eed0c484bd2752

β-alanine is the rate-limiting point for the endogenous synthesis of carnosine in skeletal muscle. Carnosine has a wide range of implications for health, normal function and exercise performance. Whilst the physiological relevance of carnosine to different tissues remains enigmatic, β-alanine administration is a useful strategy to investigate the physiological roles of carnosine in humans. Intravenous administration of β-alanine is an interesting approach to study carnosine metabolism. However, sterilisation is mandatory due to the nature of the administration route. We evaluated whether sterilising doses of gamma radiation damages the molecular structure and leads to the loss of functional characteristics of β-alanine. Pure β-alanine was sterilised by gamma radiation in sealed glass vials using a 60Co multipurpose irradiator at a dose rate of 8.5 kGy.hour-1 totalising 10, 20, 25 30 and 40 kGy. The molecular integrity was assessed by X-ray Diffraction and changes in content were determined by High Performance Liquid Chromatography (UV-HPLC) and Triple Quadrupole Mass Spectrometer (HPLC/MS-MS). Sterility assurance was evaluated by inoculation assay. To examine whether functional properties were preserved, β-alanine was infused in one participant, who rated the level of paraesthesia on the skin using a 0–3 scale. Urinary β-alanine was quantified before and 24-h following β-alanine infusion using HPLC-ESI+-MS/MS. Irradiation resulted in no change in the crystal structure of β-alanine, no degradation, and no new peaks were identified in the dose range assayed. The inoculation assay showed the absence of viable microorganisms in all β-alanine samples, including those that did not undergo irradiation. Intravenous infusion of β-alanine resulted in paraesthesia and it detected in the urine as per normal. We conclude that gamma radiation is a suitable technique for the sterilisation of β-alanine. It does not lead to degradation, damage to the β-alanine structure, content or loss of function within the evaluated irradiation conditions.

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<![CDATA[Base composition is the primary factor responsible for the variation of amino acid usage in zebra finch (Taeniopygia guttata)]]> https://www.researchpad.co/article/5c117b88d5eed0c4846998fc

In the present study, we carried out an examination of the amino acid usage in the zebra finch (Taeniopygia guttata) proteome. We found that tRNA abundance, base composition, hydrophobicity and aromaticity, protein second structure, cysteine residue (Cys) content and protein molecular weight had significant impact on the amino acid usage of the zebra finch. The above factors explained the total variability of 22.85%, 25.37%, 10.91%, 5.06%, 4.21%, and 3.14%, respectively. Altogether, approximately 70% of the total variability in zebra finch could be explained by such factors. Comparison of the amino acid usage between zebra finch, chicken (Gallus gallus) and human (Homo sapiens) suggested that the average frequency of various amino acid usage is generally consistent among them. Correspondence analysis indicated that base composition was the primary factor affecting the amino acid usage in zebra finch. This trend was different from chicken, but similar to human. Other factors affecting the amino acid usage in zebra finch, such as isochore structure, protein second structure, Cys frequency and protein molecular weight also showed the similar trends with human. We do not know whether the similar amino acid usage trend between human and zebra finch is related to the distinctive neural and behavioral traits, but it is worth studying in depth.

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<![CDATA[Uterine contractility changes in a perfused swine uterus model induced by local anesthetics procaine, lidocaine, and ropivacaine]]> https://www.researchpad.co/article/5c12cf97d5eed0c4849149f9

Background

Local anesthetics (LAs) are increasingly used as therapeutics due to their multiple molecular effects. They may be potential agents also in gynecology and reproductive medicine. The objective of this study was to investigate the contractility response of the perfused swine uterus to different concentrations of the LAs procaine, lidocaine, and ropivacaine.

Methods and findings

In an extracorporeal perfusion model with fresh swine uteri, effects of administered boli of these three LAs in concentrations of 0.1 mg/mL, 0.5 mg/mL and 1.0 mg/mL on uterine contractility and peristalsis were assessed using an intrauterine double-chip micro-catheter. A dose-dependent increase in intrauterine pressure (IUP) in the isthmus and corpus uteri was observed after the administration of the ester-LA procaine 0.1, 0.5, and 1.0%, which was not seen with lower concentrations, or buffer solution. An increase-decrease curve was found after increasing concentrations of the amide-LA lidocaine and ropivacaine, with an IUP plateau with 0.1 and 0.5%, and a decrease with 1% (p<0.01). All reactions were seen in both the isthmus and corpus uteri. The difference of the contractility pattern between ester- and amide-LA at 1% concentration was significant.

Conclusion

LAs dose-dependently modulate contractility in non-pregnant swine uteri. The amid-LAs lidocaine and ropivacaine reduce contractility in higher concentrations and may be used as therapeutics in disorders with increased uterine contractility, as dysmenorrhoea, endometriosis, and infertility. The multiple molecular effects of LAs may explain these effects. This in-vitro pilot study in vitro provides initial data for designing further studies to transfer the results onto humans.

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<![CDATA[Structural insight into substrate and product binding in an archaeal mevalonate kinase]]> https://www.researchpad.co/article/5c12cf8ed5eed0c484914932

Mevalonate kinase (MK) is a key enzyme of the mevalonate pathway, which produces the biosynthetic precursors for steroids, including cholesterol, and isoprenoids, the largest class of natural products. Currently available crystal structures of MK from different organisms depict the enzyme in its unbound, substrate-bound, and inhibitor-bound forms; however, until now no structure has yet been determined of MK bound to its product, 5-phosphomevalonate. Here, we present crystal structures of mevalonate-bound and 5-phosphomevalonate-bound MK from Methanosarcina mazei (MmMK), a methanogenic archaeon. In contrast to the prior structure of a eukaryotic MK bound with mevalonate, we find a striking lack of direct interactions between this archaeal MK and its substrate. Further, these two MmMK structures join the prior structure of the apoenzyme to complete the first suite of structural snapshots that depict unbound, substrate-bound, and product-bound forms of the same MK. With this collection of structures, we now provide additional insight into the catalytic mechanism of this biologically essential enzyme.

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<![CDATA[Binding of the general anesthetic sevoflurane to ion channels]]> https://www.researchpad.co/article/5c059df1d5eed0c4849c981e

The direct-site hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a first principle all-atom demonstration of this structure-function premise is still missing. We focus on the clinically used sevoflurane interaction to anesthetic-sensitive Kv1.2 mammalian channel to resolve if sevoflurane binds protein’s well-characterized open and closed structures in a conformation-dependent manner to shift channel equilibrium. We employ an innovative approach relying on extensive docking calculations and free-energy perturbation of all potential binding sites revealed by the latter, and find sevoflurane binds open and closed structures at multiple sites under complex saturation and concentration effects. Results point to a non-trivial interplay of site and conformation-dependent modes of action involving distinct binding sites that increase channel open-probability at diluted ligand concentrations. Given the challenge in exploring more complex processes potentially impacting channel-anesthetic interaction, the result is revealing as it demonstrates the process of multiple anesthetic binding events alone may account for open-probability shifts recorded in measurements.

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<![CDATA[Crystal structure and structure-based mutagenesis of actin-specific ADP-ribosylating toxin CPILE-a as novel enterotoxin]]> https://www.researchpad.co/article/5989db52ab0ee8fa60bdc74d

Unusual outbreaks of food poisoning in Japan were reported in which Clostridium perfringens was strongly suspected to be the cause based on epidemiological information and fingerprinting of isolates. The isolated strains lack the typical C. perfringens enterotoxin (CPE) but secrete a new enterotoxin consisting of two components: C. perfringens iota-like enterotoxin-a (CPILE-a), which acts as an enzymatic ADP-ribosyltransferase, and CPILE-b, a membrane binding component. Here we present the crystal structures of apo-CPILE-a, NAD+-CPILE-a and NADH-CPILE-a. Though CPILE-a structure has high similarity with known iota toxin-a (Ia) with NAD+, it possesses two extra-long protruding loops from G262-S269 and E402-K408 that are distinct from Ia. Based on the Ia–actin complex structure, we focused on actin-binding interface regions (I-V) including two protruding loops (PT) and examined how mutations in these regions affect the ADP-ribosylation activity of CPILE-a. Though some site-directed mutagenesis studies have already been conducted on the actin binding site of Ia, in the present study, mutagenesis studies were conducted against both α- and β/γ-actin in CPILE-a and Ia. Interestingly, CPILE-a ADP-ribosylates both α- and β/γ-actin, but its sensitivity towards β/γ-actin is 36% compared with α-actin. Our results contrast to that only C2-I ADP-ribosylates β/γ-actin. We also showed that PT-I and two convex-concave interactions in CPILE-a are important for actin binding. The current study is the first detailed analysis of site-directed mutagenesis in the actin binding region of Ia and CPILE-a against both α- and β/γ-actin.

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<![CDATA[8-Oxoguanine Affects DNA Backbone Conformation in the EcoRI Recognition Site and Inhibits Its Cleavage by the Enzyme]]> https://www.researchpad.co/article/5989d9e3ab0ee8fa60b6a672

8-oxoguanine is one of the most abundant and impactful oxidative DNA lesions. However, the reasons underlying its effects, especially those not directly explained by the altered base pairing ability, are poorly understood. We report the effect of the lesion on the action of EcoRI, a widely used restriction endonuclease. Introduction of 8-oxoguanine inside, or adjacent to, the GAATTC recognition site embedded within the Drew—Dickerson dodecamer sequence notably reduced the EcoRI activity. Solution NMR revealed that 8-oxoguanine in the DNA duplex causes substantial alterations in the sugar—phosphate backbone conformation, inducing a BI→BII transition. Moreover, molecular dynamics of the complex suggested that 8-oxoguanine, although does not disrupt the sequence-specific contacts formed by the enzyme with DNA, shifts the distribution of BI/BII backbone conformers. Based on our data, we propose that the disruption of enzymatic cleavage can be linked with the altered backbone conformation and dynamics in the free oxidized DNA substrate and, possibly, at the protein—DNA interface.

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<![CDATA[Structural Characterization of Fibrils from Recombinant Human Islet Amyloid Polypeptide by Solid-State NMR: The Central FGAILS Segment Is Part of the β-Sheet Core]]> https://www.researchpad.co/article/5989da78ab0ee8fa60b9799c

Amyloid deposits formed from islet amyloid polypeptide (IAPP) are a hallmark of type 2 diabetes mellitus and are known to be cytotoxic to pancreatic β-cells. The molecular structure of the fibrillar form of IAPP is subject of intense research, and to date, different models exist. We present results of solid-state NMR experiments on fibrils of recombinantly expressed and uniformly 13C, 15N-labeled human IAPP in the non-amidated, free acid form. Complete sequential resonance assignments and resulting constraints on secondary structure are shown. A single set of chemical shifts is found for most residues, which is indicative of a high degree of homogeneity. The core region comprises three to four β-sheets. We find that the central 23-FGAILS-28 segment, which is of critical importance for amyloid formation, is part of the core region and forms a β-strand in our sample preparation. The eight N-terminal amino acid residues of IAPP, forming a ring-like structure due to a disulfide bridge between residues C2 and C7, appear to be well defined but with an increased degree of flexibility. This study supports the elucidation of the structural basis of IAPP amyloid formation and highlights the extent of amyloid fibril polymorphism.

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<![CDATA[Predicting Thermodynamic Properties of PBXTHs with New Quantum Topological Indexes]]> https://www.researchpad.co/article/5989d9ffab0ee8fa60b736d4

Novel group quantitative structure-property relationship (QSPR) models on the thermodynamic properties of PBXTHs were presented, by the multiple linear regression (MLR) analysis method. Four thermodynamic properties were studied: the entropy (Sθ), the standard enthalpy of formation (ΔfHθ), the standard Gibbs energy of formation (ΔfGθ), and the relative standard Gibbs energy of formation (ΔRGθ). The results by the formula indicate that the calculated and predicted data in this study are in good agreement with those in literature and the deviation is within the experimental errors. To validate the estimation reliability for internal samples and the predictive ability for other samples, leave-one-out (LOO) cross validation (CV) and external validation were performed, and the results show that the models are satisfactory.

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<![CDATA[Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics]]> https://www.researchpad.co/article/5989d9f9ab0ee8fa60b71758

The auristatin class of microtubule destabilizers are highly potent cytotoxic agents against several cancer cell types when delivered as antibody drug conjugates. Here we describe the high resolution structures of tubulin in complex with both monomethyl auristatin E and F and unambiguously define the trans-configuration of both ligands at the Val-Dil amide bond in their tubulin bound state. Moreover, we illustrate how peptidic vinca-site agents carrying terminal carboxylate residues may exploit an observed extended hydrogen bond network with the M-loop Arg278 to greatly improve the affinity of the corresponding analogs and to maintain the M-loop in an incompatible conformation for productive lateral tubulin-tubulin contacts in microtubules. Our results highlight a potential, previously undescribed molecular mechanism by which peptidic vinca-site agents maintain unparalleled potency as microtubule-destabilizing agents.

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<![CDATA[Identification of key amino acid residues in the hTGR5–nomilin interaction and construction of its binding model]]> https://www.researchpad.co/article/5989db5dab0ee8fa60be0465

TGR5, a member of the G protein-coupled receptor (GPCR) family, is activated by bile acids. Because TGR5 promotes energy expenditure and improves glucose homeostasis, it is recognized as a key target in treating metabolic diseases. We previously showed that nomilin, a citrus limonoid, activates TGR5 and confers anti-obesity and anti-hyperglycemic effects in mice. Information on the TGR5–nomilin interaction regarding molecular structure, however, has not been reported. In the present study, we found that human TGR5 (hTGR5) shows higher nomilin responsiveness than does mouse TGR5 (mTGR5). Using mouse–human chimeric TGR5, we also found that three amino acid residues (Q77ECL1, R80ECL1, and Y893.29) are important in the hTGR5–nomilin interaction. Based on these results, an hTGR5–nomilin binding model was constructed using in silico docking simulation, demonstrating that four hydrophilic hydrogen-bonding interactions occur between nomilin and hTGR5. The binding mode of hTGR5–nomilin is vastly different from those of other TGR5 agonists previously reported, suggesting that TGR5 forms various binding patterns depending on the type of agonist. Our study promotes a better understanding of the structure of TGR5, and it may be useful in developing and screening new TGR5 agonists.

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<![CDATA[In silico discovery of substituted pyrido[2,3-d]pyrimidines and pentamidine-like compounds with biological activity in myotonic dystrophy models]]> https://www.researchpad.co/article/5989db5cab0ee8fa60be0332

Myotonic dystrophy type 1 (DM1) is a rare multisystemic disorder associated with an expansion of CUG repeats in mutant DMPK (dystrophia myotonica protein kinase) transcripts; the main effect of these expansions is the induction of pre-mRNA splicing defects by sequestering muscleblind-like family proteins (e.g. MBNL1). Disruption of the CUG repeats and the MBNL1 protein complex has been established as the best therapeutic approach for DM1, hence two main strategies have been proposed: targeted degradation of mutant DMPK transcripts and the development of CUG-binding molecules that prevent MBNL1 sequestration. Herein, suitable CUG-binding small molecules were selected using in silico approaches such as scaffold analysis, similarity searching, and druggability analysis. We used polarization assays to confirm the CUG repeat binding in vitro for a number of candidate compounds, and went on to evaluate the biological activity of the two with the strongest affinity for CUG repeats (which we refer to as compounds 12 and 25) in DM1 mutant cells and Drosophila DM1 models with an impaired locomotion phenotype. In particular, 12 and 25 enhanced the levels of free MBNL1 in patient-derived myoblasts in vitro and greatly improved DM1 fly locomotion in climbing assays. This work provides new computational approaches for rational large-scale virtual screens of molecules that selectively recognize CUG structures. Moreover, it contributes valuable knowledge regarding two compounds with desirable biological activity in DM1 models.

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<![CDATA[Unique 5′-P recognition and basis for dG:dGTP misincorporation of ASFV DNA polymerase X]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdcf29

African swine fever virus (ASFV) can cause highly lethal disease in pigs and is becoming a global threat. ASFV DNA Polymerase X (AsfvPolX) is the most distinctive DNA polymerase identified to date; it lacks two DNA-binding domains (the thumb domain and 8-KD domain) conserved in the homologous proteins. AsfvPolX catalyzes the gap-filling reaction during the DNA repair process of the ASFV virus genome; it is highly error prone and plays an important role during the strategic mutagenesis of the viral genome. The structural basis underlying the natural substrate binding and the most frequent dG:dGTP misincorporation of AsfvPolX remain poorly understood. Here, we report eight AsfvPolX complex structures; our structures demonstrate that AsfvPolX has one unique 5′-phosphate (5′-P) binding pocket, which can favor the productive catalytic complex assembly and enhance the dGTP misincorporation efficiency. In combination with mutagenesis and in vitro catalytic assays, our study also reveals the functional roles of the platform His115-Arg127 and the hydrophobic residues Val120 and Leu123 in dG:dGTP misincorporation and can provide information for rational drug design to help combat ASFV in the future.

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<![CDATA[A Novel Phenanthridionone Based Scaffold As a Potential Inhibitor of the BRD2 Bromodomain: Crystal Structure of the Complex]]> https://www.researchpad.co/article/5989d9fdab0ee8fa60b72cd5

Bromodomain containing proteins recognize the level of histone acetylation and regulate epigenetically controlled processes like gene transcription and chromatin modification. The BET (bromodomain and extra-terminal) family proteins, which are transcriptional co-regulators, have been implicated in the pathogenesis of cancer, neurodegenerative disorders, and defects in embryonic stem cell differentiation. Inhibitors selectively targeting the BET bromodomains can pave the path for new drug discovery against several forms of major diseases. By a rational structure-based approach, we have identified a new inhibitor (NSC127133) of the second bromodomain (BD2) of the BET family protein BRD2 using the NCI Diversity Set III library. A high-resolution crystal structure of the BRD2-BD2 in complex with this compound and in apo- form is refined to 0.91 and 0.94 Å, respectively. The compound, which is a phenanthridinone derivative, binds well to the acetyl-lysine binding pocket of BD2 and displays significant hydrophobic and hydrophilic interactions. Moreover, the atomic resolution data obtained in this study allowed us to visualize certain structural features of BD2 which remained unobserved so far. We propose that the discovered compound may be a potential molecule to develop a new library for inhibiting the BRD2-BD2 function.

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<![CDATA[Structural changes on a molecular basis of canola meal by conditioning temperature and time during pelleting process in relation to physiochemical (energy and protein) properties relevant to ruminants]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc2ee

The objectives of this study were: (1) To investigate the effects of conditioning temperature (70, 80, 90°C), time (30, 60 sec), and interaction (temperature × time) during the pelleting process on internal protein molecular structure changes of the co-products; (2) To identify differences in protein molecular structures among pellets that were processed under different conditions, and between unprocessed mash and pellets; 3) To quantify protein molecular structure changes in relation to predicted energy and protein utilization in dairy cows. The final goal of this program was to show how processing conditions changed internal feed structure on a molecular basis and how molecular structure changes induced by feed processing affected feed milk value in dairy cows. The hypothesis in this study was that processing-induced protein inherent structure changes affected energy and protein availability in dairy cattle and the sensitivity and response of protein internal structure to the different pelleting process conditions could be detected by advanced molecular spectroscopy. The protein molecular structures, amides I and II, amide I to II ratios, α-helix structure, β-sheet structure, and α to β structure ratios, were determined using the advanced vibrational molecular spectroscopy (ATR-FT/IR). The energy values were determined using NRC2001 summary approach in terms of total digestible nutrients, metabolizable and net energy for lactation. The protein and carbohydrate subfactions that are related to rumen degradation characteristics and rumen undegraded protein supply were determined using updated CNCPS system. The experiment design was a RCBD and the treatment design was a 3x2 factorial design. The results showed that pelleting induced changes in protein molecular structure. The sensitivity and response of protein inherent structure to the pelleting depended on the conditioning temperature and time. The protein molecular structure changes were correlated (P < 0.05) with energy values and protein subfractions of the pelleted co-product. The results indicated that the protein internal molecular structure had significant roles in determining energy and protein nutritive values in dairy cows. Multi-regression study with model variables selection showed that the energy and protein profiles in pelleted co-products could be predicted with the protein molecular structure profiles. This approach provides us a relatively new way to estimate protein value in dairy cows based on internal protein molecular structure profile.

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<![CDATA[Steroidal Saponins from the Rhizomes of Aspidistra typica]]> https://www.researchpad.co/article/5989da88ab0ee8fa60b9d211

Eleven new furostanol saponins, typaspidosides B-L (111), one new spirostanol saponin, typaspidoside M (12), and five known spirostanol saponins, 25S-atropuroside (13), neoaspidistrin (14), (25S)-pratioside D1 (15), 25S-aspidistrin (16) and 25S-neosibiricoside (17) were isolated from the rhizomes of Aspidistra typica Baill. The structures of the new compounds were established using 1D and 2D NMR (1H-1H COSY, HMQC, HMBC and ROESY) spectroscopy, high resolution mass spectrometry, and chemical methods. The aglycones of 13 (unusual furostanol saponins with opened E ring type), 9 and 10 (the methoxyl substituent at C-23 position) were found, identified from natural products for the first time. Moreover, the anti-HIV activities of the isolated steroidal glycosides were assessed, and compounds 13, 14, 16 and 17 exhibited high active against HIV-1.

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<![CDATA[Crystal Structure of a Ube2S-Ubiquitin Conjugate]]> https://www.researchpad.co/article/5989da65ab0ee8fa60b91ba8

Protein ubiquitination occurs through the sequential formation and reorganization of specific protein-protein interfaces. Ubiquitin-conjugating (E2) enzymes, such as Ube2S, catalyze the formation of an isopeptide linkage between the C-terminus of a “donor” ubiquitin and a primary amino group of an “acceptor” ubiquitin molecule. This reaction involves an intermediate, in which the C-terminus of the donor ubiquitin is thioester-bound to the active site cysteine of the E2 and a functionally important interface is formed between the two proteins. A docked model of a Ube2S-donor ubiquitin complex was generated previously, based on chemical shift mapping by NMR, and predicted contacts were validated in functional studies. We now present the crystal structure of a covalent Ube2S-ubiquitin complex. The structure contains an interface between Ube2S and ubiquitin in trans that resembles the earlier model in general terms, but differs in detail. The crystallographic interface is more hydrophobic than the earlier model and is stable in molecular dynamics (MD) simulations. Remarkably, the docked Ube2S-donor complex converges readily to the configuration seen in the crystal structure in 3 out of 8 MD trajectories. Since the crystallographic interface is fully consistent with mutational effects, this indicates that the structure provides an energetically favorable representation of the functionally critical Ube2S-donor interface.

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<![CDATA[On the Wiener Polarity Index of Lattice Networks]]> https://www.researchpad.co/article/5989db0aab0ee8fa60bc9e71

Network structures are everywhere, including but not limited to applications in biological, physical and social sciences, information technology, and optimization. Network robustness is of crucial importance in all such applications. Research on this topic relies on finding a suitable measure and use this measure to quantify network robustness. A number of distance-based graph invariants, also known as topological indices, have recently been incorporated as descriptors of complex networks. Among them the Wiener type indices are the most well known and commonly used such descriptors. As one of the fundamental variants of the original Wiener index, the Wiener polarity index has been introduced for a long time and known to be related to the cluster coefficient of networks. In this paper, we consider the value of the Wiener polarity index of lattice networks, a common network structure known for its simplicity and symmetric structure. We first present a simple general formula for computing the Wiener polarity index of any graph. Using this formula, together with the symmetric and recursive topology of lattice networks, we provide explicit formulas of the Wiener polarity index of the square lattices, the hexagonal lattices, the triangular lattices, and the 33 ⋅ 42 lattices. We also comment on potential future research topics.

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